CN101024084A

CN101024084A - Use of debranched starch in extrusive globurized medicine pellet

Info

Publication number: CN101024084A
Application number: CN 200610089886
Authority: CN
Inventors: A·杜基克; C·韦尔维特; J·P·雷蒙; P·A·阿尔蒂里; P·B·佛曼
Original assignee: Universiteit Gent; National Starch and Chemical Investment Holding Corp
Current assignee: Universiteit Gent; Henkel AG and Co KGaA
Priority date: 2005-05-02
Filing date: 2006-04-30
Publication date: 2007-08-29
Anticipated expiration: 2026-04-30
Also published as: BRPI0602614A; CN101024084B; ZA200603392B

Abstract

This patent pertains to the use of debranched starch in the preparation of pharmaceutical pellets by extrusion spheronization. Such excipients are useful in any dry dosage form, including tablets and capsules, for either immediate or sustained release.

Description

Take off the purposes of starch in extruding-round as a ball pill

Technical field

The present invention relates to take off the purposes of a starch (debranched starch) in passing through extruding-round as a ball preparation pill.

Background technology

Extruding-round as a ball is the known method for preparing the medicinal usage bead in the pharmaceutical field, and described bead comprises conventional and two kinds of dosage forms of controlled release.This method is based on following steps:

A) take off the plastically deformable material that starch and liquid mixing form moistening with at least a;

B) the described material of extruding obtains extrudate;

C) obtain a plurality of spheric basically pillers with extrudate is round as a ball; With

D) with described piller drying.

Except active component, such dosage form can also randomly comprise several inert substances, is called excipient, and the amount of its existence is enough to realize required effect of drugs.Usually according to their function these excipient are classified, as filler (being also referred to as filler and diluent), the binding agent that component is kept together plays the binding agent-filler of two kinds of functions and helps dosage form to break and the disintegrating agent of release of active ingredients when putting into fluid environment.

Usually, extruding-round as a ball use microcrystalline Cellulose is as main drug excipient.Yet microcrystalline Cellulose is expensive and be unsuitable for using with specific active ingredient.In addition, because can not disintegrate in gastro-intestinal Fluid based on the piller of microcrystalline Cellulose, the release of the active component that solubility is lower be extended.Because these limitation need be used for the microcrystalline Cellulose substitute that piller is produced.

The replaceability excipient has been attempted in this area, mainly is cellulose derivative, and mixture.Yet the substitute that is difficult to find microcrystalline Cellulose is used as pushing-main excipient in round as a ball.The substitute of many trials has all been failed in this, because be difficult to extruding or round as a ball, the water of difference absorbs or water-retaining property in the extrudate, low-quality size and distribution of shapes, and/or the dissolving and the release of the activating agent of difference.

In extruding-round as a ball, attempt corn starch, wheaten starch and waxy corn starch, and because the fact that unsuitable denseness and water can not distribute equably, cause round as a ball and inappropriate piller of differing from and unsatisfactory.

Surprisingly, have been found that now crystalline, take off starch provide push round as a ball in the remarkable substitute of microcrystalline Cellulose, and have remarkable feature and performance.

Summary of the invention

This patent relates to crystallization and takes off the purposes of a starch in passing through extruding-round as a ball preparation pill.Such excipient can be used for comprising any dried dosage form of tablet and capsule, is used for immediately or continues discharging.

Described starch excipient can be used as the replacing whole thing of microcrystalline Cellulose or can be used as the part substitute in conjunction with microcrystalline Cellulose and/or other cellulose derivative.

The term piller is spheric basically solid particle as used in this, its diameter can for about 100 microns to about 3mm.

The term dosage form is used with its wideest meaning as used in this, the meaning is not only and is referred to that the use excipient transmits the pharmaceutical dosage form of activating agent and comprises that tablet is (as discharging immediately, continue to discharge, controlled release, adjustment release, and effervescent), capsule, pill and granule, but also refer to the non-medicament forms of these products.

Excipient comprises inert all other components on binding agent, filler and the materia medica as used in this.

Term takes off starch as used in this, refer to by at least a can cracking starch molecule 1, the enzyme of 6-key carries out any starch of enzyme hydrolysis.

Term waxiness or low amylose mean and comprise in dried starch weight and contain the starch that is lower than 10% amylose as used in this.

The term starch that contains amylose means and comprises any starch that contains at least 10% amylose in dried starch weight as used in this.

The term high amylose starches means and comprises the starch that contains at least 50% amylose in dried starch weight as used in this.

Gelation as used in this, the meaning are to obtain ripening and lose the process of its grain structure by its starch.The particulate meaning is meant the structure of native starch, and wherein starch is not water miscible (still to small part be crystal) and have birefringence and be Maltese cross usually under polarized light.In high amylose starches, some natural granules do not present Maltese cross, especially filamentous particle.In the gelation process, starch loses birefringent characteristic and any Maltese cross that exists in its native state as used in this.

The piller aspect ratio meaning is the ratio of the minimum and maximum diameter of piller.In one embodiment, aspect ratio is about 1.

The fragility meaning is the trend that piller peels off in the operating process that causes forming dust.

The crystal starch meaning is crystalline starch, owing to its particle properties or because of the starch recrystallize that makes gelation by methods known in the art.The crystal property that can show starch by the X-ray diffraction shown in the embodiment part embodiment 6.

Description of drawings

The vitro drug release curve of the piller that contains two kinds of starch of the present invention that Fig. 1 has described to compare with microcrystalline Cellulose.

Fig. 2 has described the X-ray diffraction spectrum of starch example.

This patent relates to crystallization and takes off the purposes of a starch in passing through extruding-round as a ball preparation pill.Such excipient can be used for comprising any dried dosage form of tablet and capsule, is used for discharging immediately or continues discharging.

Starch means and comprises all starch that are derived from any natural origin, wherein any purposes that all is suitable at this as used in this.Native starch is a kind of starch of finding in nature as used in this.The starch that is derived from the plant that obtains by the standard breeding technique also is suitable, and the standard breeding technique comprises hybridization, displacement, and inversion transforms or any other comprises the gene or the chromosome engineering method of its variant.In addition, being derived from growth also is suitable from the starch of the plant of artificial mutation and above-mentioned genetic constitution variant thereof at this, wherein can produce this plant by the known standard method of mutational breeding.

Usually the source of this starch is corn, tuber, root, pod and fruit.Natural origin can be various corns (com) (corn (maize)), Semen Pisi sativi, Rhizoma Solani tuber osi, Rhizoma Dioscoreae esculentae, Fructus Musae, Fructus Hordei Vulgaris, Semen Tritici aestivi, rice, Herba bromi japonici, sago, three-coloured amaranth, Maninot esculenta crantz. (tapioca) (Maninot esculenta crantz. (cassava)), Rhizoma Marantae arundinaceae, Canna generalis Bailey and Sorghum vulgare Pers., and low amylose and high amylose starches variant.In one embodiment, low amylose contains and is lower than 5% amylose, in another embodiment, is lower than 3%, in the embodiment, is lower than 1% amylose again.In one embodiment, high amylose starches contains in dried starch weight 70% amylose at least, in the embodiment, is at least 80% again, further in the embodiment, is at least 90%.In a suitable embodiment, starch is the starch that contains amylose, and in another embodiment, high amylose starches has the amylose of at least 70% weight.

Raw starch can be dispersed into aqueous slurry and under enough temperature and pressures heating realize gelation.Although can realize gelation by any method known in the art, preferable methods is to force farinaceous size to pass through jet cooker.Jet cooker is known in the industry, comprises cure bag, and farinaceous size contacts live steam at elevated temperatures therein.In one embodiment, determine finishing of gelation by whole disintegrates of observing grain structure.The gelation process has been destroyed the association bonding of starch molecule in the raw starch granule wholly or in part.By making the starch molecule more can be near debranching enzyme, this have produced a starch molecule that is used to take off, thereby produces a starch molecule that takes off of homogeneous more.

After the starch gelling, can prepare to carry out enzyme and take off by starch solids content being adjusted to the highest possible solids content (keep low wash water and be convenient to the subsequent drying of starch) then.If starch is carried out enough hybrid process with uniform mixing enzyme and starch under the situation of high solid more, can use the more starch systems of high solid so.

Can use enzyme known in the art to take off the replaceable preparation method of propping up.For example, if use the enzyme that can act on granular starch, so just do not need gelation.Another example is to use as U.S. patent No.6, the high solid single-phase process described in 054,302.A replaceable example is to use the enzyme that is fixed on the solid support again.

The temperature and the pH that can regulate starch provide best enzymatic activity.These parameters will or not exist according to the existence of the types and sources, enzyme concentration, concentration of substrate and the inhibitor of used enzyme and change.

Any debranching enzyme (or mixture of such enzyme) all is applicable among the application.Can be used for enzyme among the present invention include but not limited in-α-1, the 6-glucan hydrolase, as amylopectase, isoamylase, or anyly can divide starch molecule 1, other endoenzyme of 6-key.In one embodiment, enzyme not only divides 1,6 key of starch, but also complete basically reservation 1, the 4-key.In one embodiment, used enzyme is an amylopectase, and in another embodiment, is isoamylase.

Use technology known in the art to carry out the enzyme hydrolysis of starch base material.Used enzyme amount depends on described enzyme, that is, and and type, source and activity and used base material and required amount of hydrolysis.In one embodiment, used enzyme amount be about starch weight about 0.01 to about 1.0%, in another embodiment, be about 0.01 to 0.3% of starch weight.

The optimal parameter of enzymatic activity will change according to used enzyme.The speed of enzymatic degradation depends on factor known in the art, comprises the type of used enzyme, enzyme concentration, and concentration of substrate, pH, temperature exists or does not have inhibitor, and the degree of modification and type.Can regulate these parameters and come the digestion rate of optimization starch base material.

In one embodiment, used enzyme is amylopectase (or debranching enzym is separated enzyme), the heat-staple enzyme that obtains from the species of bacillus.As long as there are at least two glucose units in the side chain, amylopectase is with the α in the catalysis amylopectin-1,6 key.The enzyme of bacillus amylopectase takes off in the process, and at pH5.0, the temperature of aqueous starch dispersion is 25 to 75 ℃.In the short if desired processing time, optimum temperature range is the top of this scope, 60 to 75 ℃ (if be heat-staple at the higher temperature debranching enzyme, or even higher temperature), maybe can use higher enzyme concentration.

For other parameter of enzyme reaction, preferred and best temperature range will change along with the change of other parameter that influences enzymatic activity, and as concentration of substrate and pH, these can be determined by the professional.Can add buffer agent, as acetate, phosphate, citrate, or other faintly acid salt is guaranteed to take off whole that pH is in optimum level in the process.The optium concentration of enzyme and substrate is controlled by the level of enzymatic activity, and enzymatic activity will be according to a batch enzyme source that provides can be provided, enzyme supplier and enzyme concentration and change.

Can allow enzyme handle to continue until producing the required component of taking off, and in one embodiment, all take off basically until producing; That is, use this certain enzyme and other parameter, do not produce other significantly taking off and prop up.If desired, any method measurement of taking off Zhi Chengdu process of taking off by measurement starch molecule enzyme known in the art.Continuing to carry out enzyme reaction takes off fully up to starch.Usually, enzyme reaction needs about 1 to about 24 hours, particularly about 4 to about 12 hours.Response time is depended on the type of used starch, used enzyme amount, and percent solids, the response parameter of pH and temperature.

Measure by means commonly known in the art by α-1, the concentration of the active reduction group that discharges of 6-D-glucan hydrolase is monitored and definite amount of hydrolysis.Can use of the change of other technology as monitoring viscosity, Iod R, or reaction end is determined in the change of molecular weight.When starch takes off fully, the measured value of monitoring will no longer change.Usually, when starch by weight at least about 95%, more particularly at least about 98%, the most special at least about 99% be take off the time, then starch takes off fully.Take off starch and have the average chain length of 14-25 glucose unit usually and be lower than approximately 0.2%, particularly be lower than about 0.1% α-1,6-D-glycosidic bond (connection (linkage)).That improves takes off Zhi Tongchang and will cause obtaining more crystal starch.

After finishing required starch debranching amount, can be with enzyme deactivation, for example by pH or heating.For example, the bacillus amylopectase is being higher than about 70 ℃ temperature rapid deactivation; Therefore, by the temperature with starch dispersions be increased at least 75 ℃ about 15 minutes, can stop using the reaction of amylopectase easily.Perhaps, can by with the pH regulator of starch dispersions to being lower than 3.0 and remain on this pH and made enzyme deactivation in about 30 minutes.

Take off and enzyme deactivation after, make starch crystals by methods known in the art, as by decrease (retrogradation).This can be undertaken by any method known in the art, is undertaken by starch is left standstill easily, in one embodiment, is undertaken by starch is left standstill in subambient temperature, as at refrigerator temperature.

Can use methods known in the art to collect starch, especially by extruding, filtration, centrifugal or dry, comprise spray drying, lyophilizing, flash drying or air drying, more particularly by filtering or flash drying, in a particular, by extruding or flash drying.Drying can be proceeded to the part degree, for example,, then that resulting product is further dry to the 60%-80% solid.Perhaps, starch can be dried to 100% solid, contain 10-15% moisture in dried starch weight usually.Usually decrease by control and dry to come crystallization control be important, so that obtain required degree of crystallinity, it is important for the present invention.It is also important that the processing after exsiccant method and other crystallization does not destroy crystal basically.

Can use methods known in the art to regulate the particle diameter of dry powder, include but not limited to, by agglomeration.Can obtain on average (average) (average (mean)) particle diameter in manufacture process by the particle diameter that methods known in the art are controlled dried powder, in one embodiment, mean diameter is at least about 25 microns, and is not more than about 90 microns.

Randomly, moisture be can regulate and improved flowability and compressing property realized.In order to obtain required degree of crystallinity, can use methods known in the art to come crystallization control, as decreasing by control and drying.In order to work in round as a ball process, starch is partially crystallizable at least.

In another embodiment, come the separating starch product by inorganic salt being added in the starch dispersions and 50 to 100 ℃ of culture mix.Described salt can be any known salt that can not disturb starch to decrease and help to discharge gelation moisture, makes linear starch molecule associate.Suitable salt includes but not limited to sodium sulfate, ammonium sulfate or magnesium sulfate and sodium chloride.In one embodiment, the solids content with minimum 10% adds salt in the farinaceous size of inactivation.

Starch can also be transformed, and includes but not limited to by flowing or thin boiling starch that oxidation, acid hydrolysis and enzyme hydrolysis make.These methods are well known in the art and can finish before or after taking off.

Can also be with the further modification of starch, before or after enzyme hydrolysis.Such modification can be a physical modification, enzyme modification, or chemical modification.Physical modification comprises to be sheared or the heat inhibition, for example by U.S. patent No.5, and the method described in 725,676.

Chemical modification includes but not limited to crosslinked, acetylation and organic esterified, hydroxyalkylation, phosphorylation and inorganic esterification, cation, anion, nonionic and amphion modification and succinum acidify (succination).Such modification is known in the art, for example exists Modified Starches:Properities and UsesIn, editor, Wurzburg, CRC Press, Inc., Florida (1986).

Can come purification come to remove spice and pigment in the destarching at this used any starch base material with proper characteristics by any method known in the art, described spice and pigment be naturally occurring or form in the course of processing in polysaccharide.The suitable purification process of handling starch is disclosed in this area, includes but not limited to the neutralizing treatment technology.Such purification process also can be used to take off a starch.

Take off the purification of starch composites if desired, can be by dialysis, filtration, centrifugal or any other known in the artly is used to separate and the method for concentrated starch composites is removed reaction impurities and side-product.For example, the starch that uses technology known in the art to wash degraded is removed the low molecular weight part of solubility, as oligosaccharide, obtains higher crystalline starch.In one embodiment, separate the molecular weight of close limit and make its crystallization, form how crystalline starch.

Usually according to the final use of determining resulting solution is adjusted to required pH.Usually, use technology known in the art with pH regulator to about 5.0 to about 7.5, in one embodiment, be about 6.0 to about 7.0.In addition, can redispersion or remove any short chain amylose that from starch dispersions, is precipitated out.

Starch as be used for pushing-round as a ball drug excipient has unique function.This method is based on following steps:

A) one or more are taken off a starch, mix, obtain the homogeneous mixture of dry powder form, obtain the plastically deformable material of moistening to the liquid that wherein adds appropriate amount with other excipient and/or one or more activating agents chosen wantonly;

B) in order to obtain to have the column extrudate of Len req and diameter, the mixture of step a) acquisition is pressed through the net of perforation;

C) in order to obtain the product of spherical piller form, that extrudate is round as a ball;

D) with the piller drying;

E) optional at least a activating agent is deposited on the surface of piller; With

F) optional with the piller coating.

Described starch can be as unique excipient or in conjunction with microcrystalline Cellulose and/or other cellulose derivative.In one embodiment, an amount of starch of taking off of use is the 10-100% based on plastically deformable material butt weight, is to be 60-90% in 25-95% and the 3rd embodiment in another embodiment.In another embodiment, take off starch and use as main excipient (be higher than excipient weight 50%) and in conjunction with binding agent, the amount that binding agent exists can be up to 8% of plastically deformable material butt weight.

In one embodiment, with amount binding agent is added in the preparation up to about 25%, in another embodiment, addition is up to about 15%, again in the embodiment, addition is up to about 8%, and all are measured all based on plastically deformable material butt weight, helps raw material and bears round as a ball frictional force and form bigger piller size.In one embodiment, the amount of binding agent is a 4-8% weight, based on plastically deformable material dry weight.Binding agent comprise well known in the art those, in one embodiment, it is selected from hydroxypropyl emthylcellulose, the waxy corn starch of drum dried, hydroxypropyl cellulose and polyvinylpyrrolidone, in another embodiment, it is selected from the waxy corn starch of hydroxypropyl emthylcellulose and drum dry.

Randomly, can add the surface characteristic that plasticizer improves piller, in one embodiment, addition is up to 30%, and in one embodiment, addition is up to 25%, in another embodiment, addition is up to 15%, based on plastically deformable material butt weight.In one aspect of the invention, described plasticizer is a polyhydric alcohol and in another aspect, is Sorbitol.

The liquid that adds for the moistening material that is formed for pushing can comprise materia medica used usually can the described mixture of powders of moistening any liquid substance or liquid mixture (solution or emulsion), water for example, aqueous solution with different pH, the normally used organic solvent of materia medica (for example, alcohol, chlorinated solvent and oil).In one embodiment, described liquid is water.Can use any equipment known in the art to prepare described wet material, include but not limited to planetary stirring machine, high-shear impeller, crank throw blade blender, or continuous comminutor.

Add liquid with the amount of any needs, in one aspect of the present invention, addition is 20-55%, on the other hand in addition be 30-45%, all based on the weight in wet base of plastically deformable material.

In one aspect of the present invention, activating agent and/or excipient can be dissolved in, be scattered in and/or be emulsifiable in such liquid.

In order to produce extrudate (cylindric filament), the material of moistening is pressed through the net of perforation.The hole of net determined the diameter of extrudate in one embodiment, to be about 0.2mm to 3mm, in another embodiment, is about 0.5mm about 2mm extremely.Can use single screw rod, twin screw, " screen cloth and basket (sieveand basket) " type, " roll-type extruding machine ", the extruding machine of " ram extruder " or any other medicines are gone up acceptable manner and are pushed to produce extrudate.In the embodiment of the present invention, can use the coaxial extruding machine of twin screw.

In an aspect of of the present present invention,, can before round as a ball, the material that pushes be pushed again in order to obtain the higher closely knit level of extrudate.

Then will be round as a ball by the extrudate that extruding obtains.Circle rolling device comprises the hollow cylinder with horizontal flap.Extrudate is broken into short fragment, and its upper surface at flap is transformed into piller, and in an aspect of of the present present invention, speed is extremely about 2 for about 200rpm, 000rpm.Can be with acceptable manner on any materia medica with the piller drying, as in drying at room temperature, and can in any device known in the art, finish, include but not limited to baking oven, fluid bed or microwave oven.

Starch is taken off in use to be provided and has been higher than 80% output, in one embodiment, is higher than 90%.The meaning of output is the extrusion composition that forms available piller, promptly is the percentage ratio of the particulate piller of spherical solid basically, described particulate diameter be about 100 microns to about 3mm.In one embodiment, the diameter of piller is about 0.70 to 1.40mm.From resulting piller, remove fine powder and piller as sieving by technology known in the art with non-required size.

In one embodiment, piller has 1.1 to 1.2 aspect ratio.In one embodiment, piller fragility is lower than 2%, on the other hand in, be lower than 0.5%.Piller presents disintegrate immediately and disintegrate immediately basically in artificial harmonization of the stomach intestinal juice in water-bearing media.

Can in statu quo use the piller maybe can be with its coating.In one embodiment, if activating agent is arranged in the piller, activating agent and the activating agent in the piller that coating has are identical or different.In another embodiment, with the piller coating, these functional purposes include but not limited to obtain the effect of controlled release for functional purpose, cover taste, improve storage life and are used for identifying purpose.Optional coating can contain activating agent and at least a functional component.Described piller can be used for tablet, capsule, parcel and other preparation.

Can use the compatible activating agent of various starch among the present invention.The special properties of active component is not crucial, can use medicine and non-active constituents of medicine yet, as supplementary, and detergent, dyestuff, insecticide, agricultural chemicals, enzyme and food.Typical product includes but not limited to capsule and tablet, and described capsule and tablet not only are used for medicinal usage, and are used for detergent, fertilizer, insecticide, animal feed piller, food and non-food stuff purposes.

The meaning of pharmacologic activity agent is that any physiology or pharmacology are upward acceptable, organic or inorganic, natural or synthetic source, the material of generation whole body or partial result in the organism of living.Can include but not limited to act on the unify medicine of peripheral nervous system of central nervous system by the effective ingredient of piller of the present invention carrying, cardiovascular drugs, hypotensor, diuretic, anti-inflammatory agent, analgesic, antipyretic, antiasthmatic drug, bronchodilator, antitussive, mucolytic, antibiotic, chemotherapeutics, antiviral agents, hormone, antineoplastic agent, immunosuppressant, immunostimulant, peptide, polypeptide, protein, vaccine, anti-arrhythmic, antifungal and antipsoriatic, antiviral agents, antihypertensive, antidepressant, antihistaminic, antineoplastic agent and immunosuppressant, antianxiety drugs, tranquilizer, hypnotic, beta blocker, beta-2-agonists, heart and cardiovascular inotropic agent, corticosteroid, gastrointestinal drug and anti-H2-histamine medicine, hypolipidemic, anti-anginal drug, central action medicine, vitamin and nutrient, the opium analgesic, gonadal hormone, and peptide, protein or polysaccharide molecule.

By common used technology in the field of pharmacology, include but not limited to spray drying and coating, activating agent can be distributed in piller inside and/or they can be deposited on the piller surface.

Be distributed in the situation of microgranule inside at active effective ingredient, it is about 0.1% to about 95% of a microgranule weight.

Other medicines excipient known in the art can be added gives preparation satisfied processing, disintegrate or other characteristic in the pharmaceutical dosage form.Such excipient includes but not limited to fluidity enhancers, surfactant, lubricant and fluidizer, disintegrating agent, pigment, spice and sweeting agent.These excipient are well known in the art and only are subjected to the restriction of the compatibility and desirable characteristics.

Lubricant and fluidizer comprise Talcum, magnesium stearate, calcium stearate, stearic acid, Glyceryl Behenate, mineral oil, Polyethylene Glycol, hard ester group Fumaric acid sodium, stearic acid, vegetable oil, zinc stearate and silicon dioxide.

Be applicable to that disintegrating agent of the present invention comprises starch, alginic acid, natural gum, croscarmellose (croscarmelose), polyvinylpolypyrrolidone, sodium starch glycollate, sodium lauryl sulfate, microcrystalline Cellulose, polacrilin (polacrilin) potassium, and methylcellulose.

If final required finished product is not a pharmaceutical dosage form, can there be replaceable additive well known by persons skilled in the art.For example, bathe spice in the oily tablet and the surfactant in aromatic or the detergent tablet.

Can use other prilling process known in the art that relates to high shear to form piller, comprise fluid bed and rotating granulation, centrifugal granulator, or high shear pelletize.

Provide following embodiment and further specify and explain the present invention, should not be thought of as restriction any aspect of the present invention.

1. method may further comprise the steps:

A) at least a crystallization is taken off the plastically deformable material that a starch and liquid mixing form moistening:

B) the described material of extruding obtains extrudate;

C) obtain a plurality of spheric basically pillers with described extrudate is round as a ball; With

D) with described piller drying.

2. the method for embodiment 1 is wherein propped up a starch and a liquid mixing with taking off at least a excipient and the step (a).

3. the method for embodiment 1 is wherein propped up a starch and a liquid mixing with taking off at least a activating agent and the step (a).

4. the method for embodiment 1 wherein further comprises at least a activating agent is deposited on the surface of described piller.

5. the method for embodiment 1 wherein further comprises at least a activating agent and/or functional component are coated on the described piller surface.

6. the method for embodiment 5, wherein said functional component are provided for described piller and are selected from controlled release, the function of storage life and identification is covered, improved to taste.

7. the method for embodiment 1, wherein said to take off a starch be high amylose starches starch.

8. the method for embodiment 1 wherein is to use amylopectase or isoamylase with starch debranching.

9. the method for embodiment 7, wherein said starch is the corn starch with at least 70% weight amylose content.

10. the method for embodiment 2, wherein said to take off a starch amount be the 10-100% of plastically deformable material butt weight.

11. the method for embodiment 2, wherein said excipient is a binding agent, and amount is up to about 15% of plastically deformable material butt weight.

12. the method for embodiment 11, wherein said binding agent is selected from hydroxypropyl emthylcellulose, the waxy corn starch of drum dried, hydroxypropyl cellulose and polyvinylpyrrolidone.

13. the method for embodiment 12, wherein said binding agent is selected from the waxy corn starch of hydroxypropyl emthylcellulose and drum dried.

14. the method for embodiment 2, wherein said at least a excipient is a plasticizer, and content is up to about 30% of plastically deformable material butt weight.

15. the method for embodiment 14, wherein said plasticizer is a polyhydric alcohol.

16. the method for embodiment 15, wherein said polyhydric alcohol is a Sorbitol.

17. the method for embodiment 1, wherein said amount of liquid are 20% to 55% of plastically deformable material weight in wet base.

18. the method for embodiment 1 further comprises described extrudate is pushed again.

19. the method for embodiment 1 wherein is higher than 80% piller and has about diameter of 0.70 to 1.40mm.

20. each method of embodiment 3-5, wherein said activating agent is selected from medicine, supplementary, detergent, dyestuff, insecticide, agricultural chemicals, enzyme and food.

21. each method of embodiment 3-5, wherein said activating agent is a medicine.

The specific embodiment

Embodiment

Provide following examples and further specify and explain the present invention, should not be thought of as restriction any aspect of the present invention.All used percentage ratios all are based on w/w.

Test program below in whole embodiment, all using:

Aspect ratio-use image analysis to measure the aspect ratio of each independent piller.The result represents the average aspect ratio of about 300 pillers.

Fragility-fragility value representation is for changeing the % loss in weight (initially being about 10g) of back piller quality in rotation in 10 minutes 250 in the friability determinator.In order to improve mechanical stress, 200 beades (diameter 4mm) are added in the piller piller.

Dissolution in vitro speed-for the release of testing drug, used USP XXVII dissolving test (device 2, paddle rotating speed: 50rpm) from piller.The amount of the sample of testing in the water of 900mL as dissolve medium is 300mg (is " sink conditions " of the theophylline of 8.3mg/mL according to dissolubility).Detect (maximum absorption wavelength of theophylline) at 272nm by the UV-spectrogrph.

Embodiment 1-uses amylopectase and amylomaize to prepare to take off a starch

A. will be from National Starch and Chemical Company (Bridgewater, the NYLON that NJ) buys ^VII starch, a kind of amylomaize starch, Yu Shuizhong form serosity and at 149-160 ℃ starch are carried out vapour cooking with the starch complete gelationization.Then gelatinized corn starch is remained in 60 ℃ of constant set temperature.Starch dispersions is diluted to 10% to 20% solids content.With the solution of 3: 1 water/dense HCl with pH regulator to about 5.0.When about 60 ℃ of starch temperature, add Promozyme 400L, the commercial formulation of amylopectase, NOVOZYMES, the product of Danbury Conn. makes enzyme with starch debranching 48 hours, temperature is increased to make the annealed point of solution come heat inactivation then.With 3% NaOH aqueous solution starch is neutralized to pH5.0-5.5 then.Separate by spray drying then and take off a starch.

B. repeat embodiment 1a, except by pushing drying to take off the starch.At Warner﹠amp; Push on the Pfleiderer type ZSK-30 twin (double) screw extruder.Used screw configuration is called 12-44, and uses 5mm ²Punch die.Speed at 400-450rpm is moved screw rod, and the machine barrel thermal treatment zone is set at 60 ℃/100 ℃/120 ℃/150 ℃/150 ℃.Machine barrel is placed under the vacuum of 35-40cm Hg (14-16 inch Hg) by single machine barrel outlet.

C. repeat embodiment 1a,, wherein use the bowl centrifuge of perforation, use linen as filter medium except by taking off the starch centrifugal the separation.

D. repeat embodiment 1c, use the laboratory flash drier to carry out flash drying then, inlet temperature is 250 ℃, and outlet temperature is 175 ℃, and charging rate is 7.0g/ minute.

E. repeat embodiment 1a, except before gelatinizing, using following condition 1.25% octenyl succinic anhydride with HYLON ^VII starch conversion: HYLON VII starch (800g) is formed serosity in 1200ml water.NaOH with 3% is increased to 7.4 with the pH of serosity.When keeping pH7.3-7.4, served as that the interval under agitation adds the octenyl succinic anhydride of three increments with 1/2 hour, each 3.3ml.When reaction no longer consumes caustic alkali, think to have reacted completely, and collect starch by filtering.

G. repeat embodiment 1a, except before filtering, food grade salt added take off in the starch (in the sample that separates, be 10% or 25% ammonium sulfate, 25% magnesium sulfate and 25% or 50% sodium chloride are based on the percentage ratio of starch solids).With every kind of these mixture heated to 95 ℃, and kept 24 hours in this temperature.Sample is cooled to about 25 ℃, and adding ethanol makes solvent become 50: 50 ethanol: aqueous solution, and be settled out starch product.Product is filtered by the Buchner funnel, and with 50: 50 water: twice of washing with alcohol be air drying also.

H. repeat embodiment 1a, except with 3: 1 water: the solution of dense HCl is reduced to about 3.0 with pH and makes enzyme pH inactivation 30 minutes.

I. will be from National Starch and Chemical Company (Bridgewater, the HYLON that NJ) buys ^VII starch, a kind of corn starch of high amylose starches, Yu Shuizhong form about 20% solid serosity and pH regulator is extremely about 4.0 with 3% NaOH, and 160-166 ℃ temperature vapour cooking with the starch complete gelationization.The solution of gelatinized starch is cooled to about 55 ℃, adds isoamylase then, the commercial debranching enzyme that obtains from Hayashibara (Japan), and made starch debranching 18 hours, simultaneously with temperature maintenance at 55 ℃.Use on demand 3% NaOH with pH regulator to about 5.0.In order to make enzyme deactivation and to make starch annealing, then temperature is increased to about 91-96 ℃.Then with starch cool to about 55 ℃, and use spray drying that starch is separated as powder.

A starch product is taken off in the waxy corn starch preparation that embodiment 2-uses isoamylase to take off and props up

A. the waxy corn starch that 2 kilograms of acid are transformed forms serosity in 5.4 premium on currency.By adding 3: 1 water: hydrochloric acid (HCl) is with the pH regulator to 4.0 of serosity.With 310-315  (154.4-157.2 ℃) and 80psi (5.52 * 10 ⁵Pa) the pressure decatizing vapour of back pressure carries out vapour cooking to serosity.The starch solution of gelatinizing is put into the reaction vessel of 55 ℃ of water-baths.Adding starts based on the isoamylase (buying from Hayashibara Inc.Japan) of 0.2% (wt/wt) of starch takes off by-reaction.In entire reaction course, reaction condition is maintained at 55 ℃ and pH4.0.

After reaction was carried out 5 hours, the sodium hydroxide solution with 3% was with pH regulator to 5.5.In boiling water bath, sample is heated to 85-90 ℃ then and made the isoamylase degeneration in 20 minutes.Then sample is cooled to room temperature and stirs spend the night (16 hours) in room temperature (25 ℃).Then product is filtered into starch cake and air drying.Use the test of Nelson/Somogyi reducing sugar, product has 15 the degree of polymerization (DP), and produces B-type X-ray diffraction pattern.

B. repeat the method for embodiment 1A, except sample being cooled to 40 ℃ and remain on 40 ℃ and spend the night so that crystallization, rather than beyond room temperature.Product produces A-type X-ray diffraction pattern.

C. repeat the method for embodiment 1A, except with sample 4 ℃ of crystallizations.

D. repeat the method for embodiment 1A, except making the response time carried out 24 hours rather than 5 hours.Product has 14 D.P. and produces A-type X-ray diffraction pattern.

Embodiment 3-uses low solid reaction to prepare to take off a starch product

The waxy corn starch of 1.8kg is formed serosity in 5.4 premium on currency.With 310-315  (154.4-157.2 ℃) and 80psi (5.52 * 10 ⁵Pa) the pressure decatizing vapour of back pressure carries out vapour cooking to sample.The starch solution of gelatinizing is diluted to 10% solid and puts into 55 ℃ reaction vessel.By adding 3: 1 water: HCl is with the pH regulator to 4.0 of sample.Sample temperature is maintained at 55 ℃, and adds 0.2% isoamylase and start and take off by-reaction.After sample DE reaches 7.5 (about 8 hours), pH is reduced to made enzyme denaturation in 2.0 30 minutes, be increased to 6.0 with 3% sodium hydroxide then.Then sample is cooled to room temperature and makes its crystallization spend the night (16 hours).By filtration acquisition sample cake and with the sample air drying.

Embodiment 4-uses the extruding of taking off a starch round as a ball

A. with 62.5g (25%, dry) theophylline anhydrous (Eur.Ph.), 15.0g (6%, dry) hydroxypropyl emthylcellulose (Methocel ^E15 Premium LV EP) and the dry mixture of 172.5g (69%, dry) embodiment 1a starch assembled 10 minutes with the moistening in planetary stirring machine of 200.0g (44.4%, wet material) water.Push by the extruding screen cloth with 1mm punch die opening by the dome screw extruder material that will wet then, extrusion speed is 50rpm.The wet material that will squeeze out then was the speed of 850rpm round as a ball 2 minutes 30 seconds.With the wet piller that obtains in fluid bed dry about 40 minutes, inlet air temperature was 60 ℃, until the constant weight that realizes described material.

Dried piller is sieved, obtain 86.1% output.

Aspect ratio is 1.14.

Fragility is 0.25%.Drug release characteristics is described below:

Discharge 60% theophylline after 5 minutes;

Discharge 89% theophylline after 10 minutes;

Discharge 96% theophylline after 15 minutes;

Discharge 98% theophylline after 20 minutes; With

Discharge 100% theophylline after 30 minutes.

After in their immersion dissolve mediums 15 minutes, the piller disintegrate.

B. with 62.5g (25%, dry) theophylline anhydrous (Eur.Ph.), 11.25g (4.5%, dry) hydroxypropyl emthylcellulose (Methocel ^E15 Premium LV EP), the dry mixture of 28.125g (11.25%, dry) Sorbitol and 148.25g (59.25%, dry) embodiment 1a starch was assembled 10 minutes with 148g (37%, wet material) water moistening in planetary stirring machine.Described in embodiment 4a, obtain piller.

Dried piller is sieved, obtain 87.4% output.

Aspect ratio is 1.12.

Fragility is 0.02%.The drug release curve description is as follows:

Discharge 40% theophylline after 5 minutes;

Discharge 76% theophylline after 10 minutes;

Discharge 93% theophylline after 15 minutes;

Discharge 99% theophylline after 20 minutes; With

Discharge 100% theophylline after 30 minutes.

After in their immersion dissolve mediums 10 minutes, the piller disintegrate.

C. with 17.5g (7%, dry) hydroxypropyl emthylcellulose (Methocel ^E15 Premium LVEP), the dry mixture of 25g (10%, dry) Sorbitol and 207.5g (83%, dry) embodiment 1e starch was assembled 10 minutes with water moistening in planetary stirring machine of 142g (36.2%, wet material).Push by the extruding screen cloth with 1mm punch die opening by the dome screw extruder material that will wet then, extrusion speed is 60rpm.The wet material that will squeeze out then round as a ball 3 minutes in the speed of 850rpm.The wet piller that obtains is dry in 40 ℃ baking oven, until the constant weight that realizes described material.

Dried piller is sieved, obtain 94.8% output.

Aspect ratio is 1.14.

The comparison of embodiment 5-and other starch and mixture

A. with 62.5g (25%, dry) theophylline anhydrous (Eur.Ph.), 3.75g (1.5%, dry) hydroxypropyl emthylcellulose (Methocel ^E15 Premium LV EP) and the dry mixture of 183.75g (73.5%, dry) embodiment 2a starch assembled 10 minutes with water moistening in planetary stirring machine of 125.0g (33.3%, wet material).Push by the extruding screen cloth with 1mm punch die opening by the dome screw extruder material that will wet then, extrusion speed is 70rpm.The wet material that will squeeze out then round as a ball 3 minutes in the speed of 850rpm.With the wet piller that obtains in 40 ℃ of baking ovens dry about 30 hours, until the constant weight that realizes described material.

Dried piller is sieved, obtain 73.6% output.

Aspect ratio is 1.13.

Fragility is 0.14%.

The drug release curve description is as follows:

Discharge 40% theophylline after 5 minutes;

Discharge 83% theophylline after 10 minutes;

Discharge 92% theophylline after 15 minutes;

Discharge 96% theophylline after 20 minutes;

Discharge 98% theophylline after 30 minutes; With

Discharge 100% theophylline after 45 minutes.

After in their immersion dissolve mediums 30 minutes, the piller disintegrate.

B. with 62.5g (25%, dry) theophylline anhydrous (Eur.Ph.) and 187.5g (75%, dry) microcrystalline Cellulose (Avicel ^PH101) assembled 5 minutes with water moistening in planetary stirring machine of 237.5g (48.7%, wet material).Push by the extruding screen cloth with 1mm punch die opening by the dome screw extruder material that will wet then, extrusion speed is 50rpm.The wet material that will squeeze out then was the speed of 850rpm round as a ball 2 minutes 30 seconds.With the wet piller that obtains in fluid bed dry about 40 minutes, inlet air temperature was 60 ℃, until the constant weight that realizes described material.

Fragility is 0.22%.

The drug release curve description is as follows:

Discharge 24% theophylline after 5 minutes;

Discharge 37% theophylline after 10 minutes;

Discharge 45% theophylline after 15 minutes;

Discharge 52% theophylline after 20 minutes;

Discharge 62% theophylline after 30 minutes;

Discharge 73% theophylline after 45 minutes; With

Discharge 81% theophylline after 60 minutes.

Piller does not have disintegrate in the dissolving test process.

C. in round as a ball process, attempted highly degrading, unbodied, the corn starch of 70% amylose, but can not process, because produced material viscosity, the chewing gum shape after adding entry.

D. in round as a ball process, attempted taking off an amorphous short chain amylose starch that makes, but can not process, because produced material viscosity, the chewing gum shape after adding entry by waxy corn starch.

Embodiment 6-is by the crystallization of x-ray powder diffraction working sample

Use Rigaku Miniflex x-ray diffractometer to collect the X-ray diffraction spectrum of starch sample with the continuous sweep pattern, this instrument has variable divergent slit, be 5 to 35 (sampling frequency 0.020 degree) in 2 θ/θ scope, use the Cu Kalpha radiation (0.154nm) of 30kV.The result who is shown among Fig. 2 has shown that

sample

1,2 and 5 is crystal.

Sample 1 (starch of embodiment 1i) and sample 2 (starch of embodiment 1a) all demonstrate typical B type crystal structure diffraction pattern.Sample 3 (sample of embodiment 5d) and sample 4 (sample of embodiment 5c) all present the wide curve of typical amorphous starch, and maximum is at about 20 degree 2 θ places.Last sample (sample of embodiment 1e) demonstrates faint peak, is the starch that typically has little degree of crystallinity.

Claims

1. method may further comprise the steps:

A) at least a crystallization is taken off the plastically deformable material that a starch and liquid mixing form moistening;

B) the described material of extruding obtains extrudate;

D) with described piller drying.

2. the process of claim 1 wherein a starch and the liquid mixing of taking off at least a excipient and the step (a).

3. claim 1 or 2 method are wherein with a taking off starch and the liquid mixing at least a activating agent and the step (a).

4. each method of claim 1-3 further comprises at least a activating agent is deposited on the surface of described piller.

5. each method of claim 1-4 further comprises at least a activating agent and/or functional component are coated on the described piller surface.

6. the method for claim 5, wherein said functional component are provided for described piller and are selected from controlled release, the function of storage life and identification is covered, improved to taste.

7. each method of claim 1-6, wherein said to take off a starch be high amylose starches starch.

8. each method of claim 1-7 wherein is to use amylopectase or isoamylase with starch debranching.

9. the method for claim 7, wherein said starch is the corn starch with at least 70% weight amylose content.

10. each method of claim 1-9, wherein said to take off a starch amount be the 10-100% of plastically deformable material butt weight.

11. each method of claim 2-10, wherein said excipient is a binding agent, and amount is up to about 15% of plastically deformable material butt weight.

12. the method for claim 11, wherein said binding agent is selected from hydroxypropyl emthylcellulose, the waxy corn starch of drum dried, hydroxypropyl cellulose and polyvinylpyrrolidone.

13. the method for claim 12, wherein said binding agent is selected from the waxy corn starch of hydroxypropyl emthylcellulose and drum dried.

14. each method of claim 2-10, wherein said at least a excipient is a plasticizer, and content is up to about 30% of plastically deformable material butt weight.

15. the method for claim 14, wherein said plasticizer is a polyhydric alcohol.

16. the method for claim 15, wherein said polyhydric alcohol is a Sorbitol.

17. each method of claim 1-16, wherein said amount of liquid is 20% to 55% of a plastically deformable material weight in wet base.

18. each method of claim 1-17 further comprises described extrudate is pushed again.

19. each method of claim 1-18 wherein is higher than 80% piller and has about diameter of 0.70 to 1.40mm.

20. each method of claim 3-19, wherein said activating agent is selected from medicine, supplementary, detergent, dyestuff, insecticide, agricultural chemicals, enzyme and food.

21. each method of claim 3-19, wherein said activating agent is a medicine.